Fanconi anemia complementation group A cells are hypertensive to chromium(VI)-induced toxicity
Environmental Health Perspectives
Apoptosis; Carcinogen; Caspase-3; Clonogenicity; DNA adducts; Genotoxin; Phosphatidylserine translocation; Sodium chromate; Uptake
Fanconi anemia (FA) is an autosomal recessive disorder characterized by diverse developmental abnormalities, progressive bone marrow failure, and a markedly increased incidence of malignancy. FA cells are hypersensitive to DNA cross-linking agents, suggesting a general defect in the repair of DNA cross-links. Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory carcinogens and induce several types of DNA lesions, including ternary DNA-Cr-DNA interstrand cross-links (Cr-DDC). We hypothesized that human FA complementation group A (FA-A) cells would be hypersensitive to Cr(VI) and Cr(VI)-induces apoptosis. Using phosphatidylserine translocation and caspase-3 activation, human FA-A fibroblasts were found to be markedly hypersensitive to chromium-induced apptosis compared with CRL-1634 cells, which are normal human foreskin fibroblasts (CRL). The clonogenicity of FA-A cells was also significantly decreased compared with CRL cells after Cr(VI) treatment. There was no significant difference in either Cr(VI) uptake or Cr-DNA adduct formation between FA-A and CRL cells. These results show that FA-A cells are hupersensitive to Cr(VI) and Cr-incuced apoptosis and that this hupersensitivity is not due to increased Cr(VI) uptake or increased Cr-DNA adduct formation. The results also suggest that Cr-DDC may be proapoptotic lesions. These results are the first to show that FA cells are hypersensitive to an environmentally relevant DNA cross-linking agent.
Vilcheck, S., O'Brien, T., Pritchard, D., Ha, L., Ceryak, S., Fornsaglio, J., & Patierno, S. (2002). Fanconi anemia complementation group A cells are hypertensive to chromium(VI)-induced toxicity. Environmental Health Perspectives, 110 (SUPPL. 5). http://dx.doi.org/10.1289/ehp.02110s5773